Persistent Airway Uric Acid is Associated with Epithelial Stress Signaling and Macrophage Inflammatory Activation in COPD.

BACKGROUND

Uric acid has been widely studied as a systemic biomarker in pulmonary diseases; however, serum levels are strongly influenced by medication and systemic metabolic status. Whether airway-localized uric acid contributes to epithelial dysfunction in chronic obstructive pulmonary disease (COPD) remains unclear. This study investigated the relationship between persistent mucosal uric acid and epithelial stress signaling, barrier-associated alterations, and macrophage inflammatory activation during acute exacerbations of COPD.

METHODS

Paired serum and induced sputum samples were collected from 192 patients with acute exacerbation of COPD (AECOPD) and 194 patients with community-acquired pneumonia (CAP) at baseline and 14 days after therapy. Uric acid concentrations were measured longitudinally. BEAS-2B airway epithelial cells were exposed to uric acid concentrations (200 μg/mL), a concentration corresponding to levels observed in AECOPD sputum. RNA sequencing was performed using three biological replicates per group, followed by Ingenuity Pathway Analysis. Key translational regulators and epithelial barrier-associated proteins were validated by qPCR and Western blotting. Epithelial-macrophage interaction was evaluated using a Transwell co-culture system with cytokine quantification by ELISA.

RESULTS

Sputum uric acid was significantly higher in AECOPD (median 120.6 μmol/L) compared with CAP controls and remained elevated after therapy, despite normalization of serum uric acid. In BEAS-2B cells, uric acid exposure induced inflammatory cytokine expression without detectable cytotoxicity. Canonical NF-κB and inflammasome activation were not observed. Transcriptomic analysis identified 2,092 differentially expressed genes and revealed suppression of EIF2 signaling and GCN2-mediated amino acid sensing, indicating activation of epithelial stress responses. Uric acid exposure was associated with altered eIF2α signaling and reduced expression of the tight-junction protein ZO-1, indicating impaired epithelial barrier integrity. In the Transwell co-culture system, macrophages exposed to uric acid-stimulated epithelial signaling showed increased secretion of pro-inflammatory cytokines.

CONCLUSION

Persistent airway uric acid may act as a compartment-specific metabolic stressor in COPD, altering epithelial translational stress signaling and barrier-associated ZO-1 expression while promoting macrophage inflammatory activation.